tbuckley/cabot-search huggingface dataset:
MODL-05. DISCOVERY OF DYNAMIC MINIMAL RESIDUAL DISEASE STATES IN ADULT GLIOBLASTOMA USING SINGLE CELL TECHNOLOGY
Authors: Zsolt Zador, Nicholas Mikolajewicz, Hong Han, Mathew Voisin, Chitra Venugopal, Chirayu Chokshi, Will Maich, Moffat Jason, Gelareh Zadeh, Sheila Singh
Journal: Neuro-Oncology (2022)

Abstract Persister states are proposed oncogenic substrates of disease recurrence in cancer. Recent concepts suggest persisters may occur in dynamic states of the cell cycle (such as cycling and non-cycling states). We therefore investigated biological programs at the post-treatment minimal residual disease (MRD) state following standard chemoradiotherapy in patient-derived xenograft models of GBM. Our analysis of single cell RNA sequencing (scRNA-seq) data from 2704 tumor cells (929 cells post treatment, 1775 matched controls) yielded a cellular profile for non-cycling and cycling persister states. We validated these programs in 3 independent scRNA-seq datasets of human glioblastoma specimens consisting of over 16,000 cells from various genetic backgrounds, including an internal two patient-matched primary and recurrent GBM pairs with over 13,000 cells. Finally, we determined that clones identified based on large scale chromosomal rearrangements converge on previously identified persister states including the dynamic states discovered in our study. Our results provide new evidence towards dynamic persister states in glioblastoma, further analysis of these dynamic states is critical to targeting this incurable disease.
CTNI-65. INTUITT-NF2, AN ADAPTIVE PLATFORM-BASKET TRIAL FOR NEUROFIBROMATOSIS 2 PATIENTS WITH PROGRESSIVE TUMORS: INTERIM RESULTS OF THE BRIGATINIB TREATMENT ARM
Authors: Scott Plotkin, Jeffrey Allen, Dusica Babovic-Vuksanovic, Christine Dinh, Leia Nghiemphu, Lorenzo Trippa, Kaleb Yohay, Jaishri Blakeley
Journal: Neuro-Oncology (2022)

Abstract Neurofibromatosis type 2 (NF2) predisposes affected individuals to vestibular schwannomas (VS), non-vestibular schwannomas (NVS), meningiomas, and ependymomas. We developed an adaptive platform-basket trial to screen multiple drugs against any type of progressive NF2-related tumor. We report the interim analysis of the first treatment arm with brigatinib, an ALK inhibitor that inhibits multiple tyrosine kinases. We conducted a multicenter, phase II, open-label study for subjects ≥12 years old with NF2 and progressive target tumors (baskets: VS, NVS, meningioma, or ependymoma). Up to 5 non-target tumors were followed in each participant. In stage 1, 20 participants (minimum of 2 participants per basket) were treated with brigatinib 180 mg daily. Tumor response was evaluated by MRI every 3 months in year 1 and every 6 months thereafter. Radiographic response (RR) was defined as ≥20% decrease in target tumor volume from baseline. The primary outcome was RR rate. Per protocol, the brigatinib arm would be discontinued if no target tumor achieved a RR at interim analysis. Twenty subjects (median age=25 years, 7 pediatric, 12 females) were treated. Target tumors included 10 VS, 3 NVS, 5 meningiomas, and 2 ependymomas; non-target tumors included 18 VS, 36 NVS, and 14 meningiomas. RR rate for target and non-target tumors was 5% and 22%, respectively. By tumor basket, RR was 28% for meningioma, 26% for non-VS, 4% for VS, and 0% for ependymomas. Annualized tumor growth rates decreased for VS, NVS, and meningioma during treatment. Brigatinib was well tolerated with one dose reduction and one discontinuation due to grade 2 diarrhea. Brigatinib treatment was associated with RR in meningiomas, VS, and NVS. In stage 2, the study will enroll 20 participants in the two most promising baskets (meningioma and NVS). This novel design provides unique ability to assess treatments for hereditary syndromes with multiple primary tumors.
PATH-38. DISSEMINATED “MYXOID GLIONEURONAL TUMOR, PDGFRA P. K385-MUTANT” IN AN ADOLESCENT MANAGED WITH OBSERVATION AND WITHOUT ANY ADJUVANT THERAPY
Authors: Magimairajan Issai Vanan, Patrick Macdonald, Cielle Wachnian, Francesca Gianno, Tina Drimes, Namita Sinha, Lili-Naz Hazrati, John Bonanni
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Myxoid glioneuronal tumor, PDGFRA p. K385-mutant (MGNT) is a recently described central nervous system tumor entity typically arising from the septum pellucidum and molecularly defined by mutation of the PDGFRA oncogene. The tumor is clinically benign, can be disseminated at presentation and is managed by surgical resection with or without adjuvant therapy (Chemotherapy / Radiation). CASE REPORT: 16yr old female presented to the children’s emergency with 6-week history of increasing intensity of acute on chronic frontal headaches and single episode of seizure like activity. She did not have nausea, vomiting or any cognitive or visual disturbances. Neurological exam was normal with no evidence of papilledema. Magnetic Resonance imaging (MRI) of the brain showed a large intraventricular mass arising from the right lateral ventricle and the septum pellucidum with dissemination into the periventricular white matter, suprasellar region, right thalamus, genu and splenium of the corpus callosum and multiple foci seen in the inferior aspect of the brain stem involving the pons and medulla. There was no evidence of obstructive hydrocephalus and the spine was normal. After an initial endoscopic biopsy failed molecular testing, she underwent an open biopsy which confirmed the diagnosis of MGNT histologically and NGS testing of the tumor revealed mutation at codon 385 (leucine replacing lysine) in the PDGFRA oncogene (k385l). Since the tumor was disseminated and the headache was controlled with symptomatic treatment, she was managed with regular follow up without surgery, adjuvant chemotherapy or radiation. The patient is doing well at 8 months follow up without any symptoms and stable lesions on the MRI. CONCLUSION Based on our experience and literature review, MGNT with PDGFRA-k385l mutation is a clinically benign tumor even though it can be disseminated at presentation and can be managed conservatively without any adjuvant therapy.
CNSC-10. THE COMPLEX RELATIONSHIP BETWEEN NEURONAL ACTIVITY AND FUNCTIONAL NETWORK PROPERTIES IN GLIOMA PATIENTS
Authors: Mona Zimmermann, Lucas Breedt, Eduarda Centeno, Shanna Kulik, Fernando Santos, Cornelis Stam, Marike van Lingen, Arjan Hillebrand, Linda Douw
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Glioma is associated with pathologically high peritumoral neuronal activity, which associates with faster tumor progression. Concurrently, glioma patients have local and widespread disturbances of the functional brain network as measured with magnetoencephalography (MEG), such as higher network clustering (the extent to which regions connected to a particular area are also connected to each other) and locally altered integrative connectivity (for instance assessed with a centrality measure). How local neuronal activity and nodal network properties relate to each other has yet to be investigated. METHODS We obtained eyes-closed resting-state MEG in 95 de novo glioma patients and 57 matched healthy controls (HCs). The offset of the power spectrum was calculated for 210 cortical atlas regions as a proxy for neuronal activity. Regional clustering coefficient (CC) and eigenvector centrality (EC) were calculated in the delta, theta and alpha bands. Offset and network values were then averaged across peritumoral regions, contralateral homologue regions and all non-peritumoral regions. Linear mixed models were used to relate nodal CC and EC to local offset in patients and HCs. RESULTS The peritumoral area was significantly more active than the non-peritumoral homologue in patients, and showed pathologically high activity in comparison to HCs. However, patients’ functional network was disturbed globally, showing higher clustering and lower centrality than HCs. Whereas high activity related to high centrality in HCs and patients alike, high activity seemed to relate to low clustering in non-peritumoral regions in patients, but not HCs. CONCLUSION We find that the relationship between neuronal activity and functional network properties is disturbed in a complex manner in glioma patients. Our results further underline the importance of investigating how local activity may impact global network topology in order to understand how neuron-glioma interactions shape brain functioning.
RADT-07. RADIOGRAPHIC “NECROSIS" FOLLOWING SINGLE-FRACTION SRS AND IMMUNE CHECKPOINT INHIBITION IS ASSOCIATED WITH IMPROVED SURVIVAL IN PATIENTS WITH BRAIN METASTASES: AN INTERNATIONAL MULTICENTER STUDY
Authors: Eric Lehrer, Manmeet Ahluwalia, Jason Gurewitz, Kenneth Bernstein, Douglas Kondziolka, Zhishuo Wei, Ajay Niranjan, L Dade Lunsford, Kareem Fakhoury, Chad Rusthoven, David Mathieu, Claire Trudel, Timothy Malouff, Henry Ruiz-Garcia, Phillip Bonney, Lindsay Hwang, Cheng Yu, Gabriel Zada, Samir Patel, Christopher Deibert, Piero Picozzi, Andrea Franzini, Luca Attuati, Rahul Prasad, Raju Raval, Joshua Palmer, Cheng-Chia Lee, Huai-che Yang, Brianna Jones, Sheryl Green, Jason Sheehan, Daniel Trifiletti
Journal: Neuro-Oncology (2022)

Abstract OBJECTIVE Immune checkpoint inhibitors (ICI) and stereotactic radiosurgery (SRS) are commonly utilized in the management of brain metastases. Treatment-related imaging changes (TRIC) are a frequently observed clinical manifestation and are commonly classified as radiographic radiation necrosis. However, these findings are not well characterized and may predict for response to SRS and ICI. METHODS The diagnosis-specific graded prognostic assessment was used to guide variable selection. TRIC were determined based upon MRI, PET/CT, or MR spectroscopy and a consensus by local clinical providers was required. RESULTS The analysis included 697 patients with 4,536 brain metastases across 11 institutions in 4 countries. The median follow-up after SRS was 13.6 months. The median age was 66 years, 54.1% of patients were male, and 57.3%, 36.3%, and 6.4% were non-small cell lung cancer, melanoma, and renal cell carcinoma (RCC) histology, respectively. TRIC were observed in 9.8%. On univariable analysis, Karnofsky Performance Status (KPS) (hazard ratio [HR]: 0.98; p &amp;lt; 0.001), presence of TRIC (HR: 0.67; p = 0.03), female sex (HR: 0.67; p &amp;lt; 0.001), and prior resection (HR: 0.60; p = 0.03) were associated with improved OS. On multivariable analysis, KPS (HR: 0.98; p &amp;lt; 0.001) and the presence of TRIC (HR: 0.66; p = 0.03) were associated with improved OS. A V12 Gy ≥ 10 cm3 (Odds Ratio [OR]: 2.78; p &amp;lt; 0.001), prior whole brain radiation therapy (OR: 3.46; p = 0.006), and RCC histology (OR: 3.10; p = 0.01) were associated with an increased probability of developing TRIC. The median OS in patients with and without TRIC was 29.0 and 23.1 months, respectively (log-rank p = 0.03). CONCLUSION TRIC following ICI and SRS are associated with a median OS benefit of approximately 6 months. Further prospective study is warranted to further elucidate the role and etiology of this common clinical scenario.
DNAR-07. BET PROTEIN INHIBITION SENSITIZES GLIOBLASTOMA CELLS TO TEMOZOLOMIDE TREATMENT BY ATTENUATING MGMT EXPRESSION
Authors: Alessandro Tancredi, Olga Gusyatiner, Pierre Bady, Michelle Buri, Rémy Lomazzi, Davide Chiesi, Monika Hegi
Journal: Neuro-Oncology (2022)

Abstract Bromodomain and extra-terminal tail (BET) proteins have been identified as potential epigenetic targets in cancer, including glioblastoma. These epigenetic modifiers link the histone code to gene transcription that can be disrupted with small molecule BET inhibitors (BETi). With the aim of identifying rational combination treatments for glioblastoma, we analyzed BETi-induced differential gene expression in glioblastoma derived-spheres. This identified 6 distinct expression patterns. To uncover emerging actionable vulnerabilities that can be targeted with a second drug, we extracted the significantly disturbed DNA Damage Response genes. Among the constantly downregulated candidates was the O-6-methylguanine-DNA methyltransferase (MGMT) gene, a known resistance factor for alkylating agent therapy in glioblastoma. BETi not only reduced MGMT expression in GBM cell lines, but also inhibited its induction, typically observed upon temozolomide treatment. To determine the potential clinical relevance, we evaluated the specificity of the effect on MGMT expression and MGMT mediated treatment resistance to temozolomide. BETi-mediated attenuation of MGMT expression was associated with reduction of BRD4- and Pol II-binding at the MGMT promoter. On the functional level, we demonstrated that ectopic expression of MGMT under an unrelated promoter was not affected by BETi, while under the same conditions, pharmacologic inhibition of MGMT restored the sensitivity to temozolomide, reflected in an increased level of gammaH2AX. Importantly, members of the mismatch repair pathway, required for sensitivity to unrepaired O6G-lesions, namely MSH6 and MSH2, were only transiently affected by BETi. Taken together, the addition of BET-inhibitors to the current standard of care, comprising temozolomide treatment, may improve the outcome of the 50% of patients whose GBM exert an unmethylated MGMT promoter.
INNV-24. PATIENT SATISFACTION AND COST ANALYSIS OF THE TELEMEDICINE PROGRAM WITHIN A NEURO-ONCOLOGY PROGRAM
Authors: Arkady Bilenkin, Richard Kang, Rachel Prorok, Andrea Rogers, Cristina Naso, Krupal Patel, Andre Beer-Furlan, James Liu
Journal: Neuro-Oncology (2022)

Abstract Unique challenges exist in the utilization of telemedicine for neurological and surgical specialties. We examined the differences in patient satisfaction for telemedicine versus in-person Press Ganey survey reports within an integrated Neuro-Oncology Department to assess whether there was a difference between surgical and medical specialties. We also examined the potential cost savings benefits of utilizing telemedicine. 1189 Press Ganey surveys in the Department of Neuro-Oncology (982 in-person and 207 telemedicine) submitted by neurosurgical and neuro-oncology patients between 04/01/2020 and 06/30/2021 were analyzed. Survey results were divided into 4 categories (Access, Provider, Technology (for telemedicine only), and Overall Satisfaction). Results were compared between telemedicine and in-person visits, and by gender, age, insurance, and specialty. Potential time and cost savings were estimated by calculating lost productivity based on census income data with motor vehicle expenses, and round-trip distances with mean visit durations, respectively. The survey results demonstrated that, among telemedicine patients, there were no differences in satisfaction based on gender, age, or insurance. Surgical specialties scored higher in Access, Technology, and Overall. Among in-person patients, patients older than 65 had higher satisfaction for Provider (p=0.0368) and Overall (p=0.0010). Medicare patients returned higher scores compared to non-private insurance for Overall (p=0.0172). Surgical patients scored higher for Access (p=0.0002). When comparing Telemedicine to In-Person scores, In-person satisfaction was higher for Provider for all patients combined. For surgical patients only, Telemedicine scored higher only in Access (p=0.0252). Cost analysis demonstrated that patients saved an average of 155.4 to 175.1 miles and 3.1 to 3.4 hours of travel per visit and average cost savings were $117.84 to $185.00. We conclude that telemedicine lessens the financial and time burden on neuro-oncology patients and yields non-inferior patient-satisfaction when employed in neurosurgery as compared to medicine, despite potential limitations of the technology in neurological and surgical specialties.
EXTH-10. TARGETING MITOCHONDRIAL ENERGETICS REVERSES THERAPEUTIC RESISTANCE IN PEDIATRIC DMG AND HGG
Authors: Matthew Reslink, Esther Jane, Daniel Premkumar, Taylor Gatesman, Stacy Wendell, Sameer Agnihotri, Ian Pollack
Journal: Neuro-Oncology (2022)

Abstract Diffuse midline gliomas (DMGs) and other high-grade gliomas (HGG) are the most commonly lethal intrinsic brain tumors of childhood. Accordingly, novel treatment approaches are needed that consider the heterogeneity of these tumors. Using an extensive pharmacological screen, we identified several two-drug combinations that were particularly effective against a range of DMG and HGG cell lines, the most active being the combination of the histone deacetylase inhibitor, panobinostat, and a proteasome inhibitor, marizomib, both in clinical trials, which synergistically induced tumor-specific apoptosis. However, at clinically achievable concentrations, a small population of resistant tumor cells survived and dominated, mimicking the clinical scenario, which prompted our development of drug resistance models as mechanistic tools. Resistance mechanisms were examined using RNA sequencing of drug-resistant versus -naïve cells. NMNAT2, a critical mediator of NAD synthesis, was overexpressed in DIPGs in the context of high baseline QPRT expression, suggesting a critical role of NAD synthesis and utilization pathways in resistance. Gene-set enrichment analysis suggested a key role for glycolytic pathways in the resistance phenotype. In support of this hypothesis, we observed increased levels of mitochondrial mass and NAD and ATP in resistant cells compared to drug-naïve cells, as well as upregulation of glycolytic intermediates by LC/MS. Conversely, inhibition of OXPHOS and glycolysis pathways resensitized resistant glioma cells to apoptosis in vitro. To test this hypothesis in vivo, mice were injected with drug-naïve or resistant DIPG-013 glioma cells and were exposed to an OXPHOS and glycolysis inhibitor, lonidamine. Lonidamine alone extended survival of naïve (18.6 + 1.4 d vs. 25 + 1.6 d, p=0.0003) and resistant (18.7 + 1 d vs. 62 + 1 d, p=0.0002) DIPG13p models (Log-Rank). This supports the application of metabolic therapy as a novel strategy for treating resistant MGs that has activity in a clinically relevant DIPG model. Supported by NIHS10OD023402, the DIPG/DMG Collaborative, the CNI, and Connor’s Cure.
STEM-20. ROLE OF CELLULAR PRION PROTEIN IN TEMOZOLOMIDE RESISTANCE OF GLIOBLASTOMA STEM CELLS
Authors: Rebeca Iglesia, Mariana Prado, Rodrigo Alves, Deanna Tiek, Anshika Goenka, Xiao Song, Bo Hu, Bo Hu, Marilene Lopes
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma (GBM), the most aggressive type of brain tumor, is initiated and maintained by a subpopulation of tumorigenic cells called glioblastoma stem cells (GSCs) that contribute to progression and resistance to therapy. In GBM therapy the alkylating agent temozolomide (TMZ) is the most effective chemotherapist, but resistance is frequent, especially in GSCs located in hypoxia niches. One of the mechanisms of resistance to TMZ involves the modulation of MGMT, which promotes cell survival through the induction of antiapoptotic proteins expression and can be regulated by hypoxia inducible factors (HIFs). Recent data from our group demonstrate that blocking the interaction between the cellular prion protein (PrPC) and one of its main ligands, the heat shock organizing protein (HOP) with a HOP peptide (HOP230-245) can inhibit GSCs self-renewal and glioblastomas growth in vivo. PrPC silencing decreases the expression of stem cells markers, self-renewal, and tumorigenesis of GSCs. Remarkably, a PrPC peptide which mimics HOP binding site (PrPC106-126) can promote HIF1α expression, inducing protection against cell death. Considering these data together, this study aims to identify the participation of PrPC in the TMZ resistance of GSCs mediated by HIF1α. In addition, we will evaluate HOP230-245 peptide potential in sensitizing GSCs to TMZ, since it binds to PrPC at the specific site 106-126 being able to compete with other PrPC ligands by this domain and, consequently, inhibit functions modulated by these interactions. Preliminary trials on stem cell enriched glioblastoma lineage cultures suggest that treatment with TMZ associated HOP230-245 increases cell death compared to TMZ or the peptide alone, sensitizing cells to TMZ treatment and increasing their efficiency. Finally, the search for therapeutic-combined strategies targeting GSCs is imperative to improve the efficacy of treatments against this incurable tumor.
CTNI-30. LOGGIC/FIREFLY-2: A PHASE 3, RANDOMIZED TRIAL OF TOVORAFENIB VS. CHEMOTHERAPY IN PEDIATRIC PATIENTS WITH NEWLY DIAGNOSED LOW-GRADE GLIOMA HARBORING AN ACTIVATING RAF ALTERATION
Authors: Cornelis van Tilburg, David T Jones, Rene Schmidt, Shivaram Avula, Antoinette Schouten- van Meeteren, Astrid Sehested, Enrico Opocher, Pablo Hernáiz Driever, Ruth Witt, David Ziegler, Samuel Blackman, Xin Zhao, Li-Pen Tsao, Michael Cox, Darren Hargrave, Olaf Witt
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Genomic alterations and dysregulation of RAF are the main oncogenic driver in almost all pediatric low-grade gliomas (pLGGs). About 50%‒60% of pLGGs harbor KIAA1549-BRAF fusion and 5%‒15% BRAF V600E mutation. No targeted therapy has received regulatory approval for either relapsed or newly diagnosed pLGG to date. Tovorafenib is an investigational, oral, selective, CNS-penetrant, small molecule, type II panRAF inhibitor. The registrational, phase 2 FIREFLY-1 (NCT04775485) study with tovorafenib in pediatric patients with recurrent/progressive LGG is currently ongoing. METHODS LOGGIC/FIREFLY-2 (EudraCT 2022-001363-27) is a registrational, randomized, multicenter, global (~100 sites across Australia, Canada, Egypt, Europe, New Zealand, Singapore, South Korea, Taiwan, and USA), phase 3 trial evaluating the efficacy, safety, and tolerability of tovorafenib vs. standard of care (SoC) chemotherapy in patients &amp;lt; 25 years old with LGG harboring a RAF-alteration and requiring first-line systemic therapy. Approximately 400 patients will be randomized 1:1 to receive oral tovorafenib, 420 mg/m2 ( ≤ 600 mg) weekly (tablet or liquid suspension for 26, 28-day cycles), or an investigator’s choice of SoC chemotherapy: COG-V/C regimen (60 weeks), SIOPe-LGG-V/C (81 weeks) regimen, or single-agent vinblastine (70 weeks). After completing 26 cycles tovorafenib, patients may continue tovorafenib or opt to enter a drug holiday at any point. Patients who progress in the SoC arm may receive tovorafenib. Patients who progress after stopping tovorafenib may be re-challenged. Primary endpoint is ORR based on RANO criteria, as determined by an independent radiology committee. Key secondary endpoints are progression-free survival and duration of response per RANO criteria, and ORR per RAPNO criteria. Other secondary endpoints include changes in neurological and visual function, and safety and tolerability. Exploratory objectives include quality of life and health utilization measures, molecular biomarker evaluation for treatment response and resistance, efficacy of tovorafenib after progression on chemotherapy and retreatment upon progression during drug holiday.